In the aged macaque senile plaques (SP) occur in large numbers, which in some monkeys achieve a density comparable to that found in Alzheimer's disease. The morphology of these SPs are comparable to those found in human aging and in Alzheimer's disease and develop without the confounding variable of the neurofibrillary tangle (NFT). The monkey thus permits the correlation of the SP (without the NFT) with changes in neuronal cell populations in subcortical nuclei that project to the cerebral cortex and with age related cognitive decline. In this project we will test the hypotheses that 1) SP accumulate with age in regionally specific patterns, 2) brain stem nuclei that project to the cerebral cortex will show neuronal cell loss in relationship to cortical SP development, and 3) age related cognitive decline is associated with SP development. To test these hypotheses we will perform a semiquantitative and quantitative assessment of the topography, distribution, morphology and immunohistochemical characteristics (amyloid, tau, etc.) of the SP in specific cytoarchitectonic regions of the prefrontal cortex, limbic temporal areas, and a more general survey throughout the cerebral cortex. In the subcortical nuclei we will perform quantitative studies of neuronal numbers in the substantia nigra, locus coeruleus and the nucleus raphe dorsalis. These data will also be used for correlation with behavioral studies (Project l, ultrastructural changes in prefrontal cortex (Project 3), alterations in the limbic cortices and basal forebrain (Project 4) and biochemical changes (Projects 5 and 6). In addition, the brain will be surveyed in serial section incidental pathology and other age related changes.